Gamma-hydroxybutyric acid (or GHB) is regarded as an endogenous neuromodulator or neurotransmitter present in the human brain. It is a metabolite of Gamma-aminobutyric acid (GABA).
Thus the medicament Xyrem® comprising as active constituent a sodium salt of GHB, namely sodium hydroxybutyrate (or sodium oxybate, Na-GHB), is used for the treatment of narcolepsy in adult patients exhibiting cataplexy.
GHB is also used as an anaesthetic.
It also has an alcohol-mimetic effect on the central nervous system. Thus clinical studies have already shown the effectiveness of GHB in the treatment of alcohol dependency.
However, the major drawback of GHB in terms of effectiveness is linked to its pharmacokinetic profile. For GHB has a short half life, a high plasma concentration peak, with fast elimination and variable (low) bioavailability as a function of feeding. For example, it is known that sodium hydroxybutyrate is absorbed very quickly by the gastroenteric system with a maximum peak of approximately 30-45 minutes after its administration and that it has a half life of approximately 20-25 minutes. Moreover, it is eliminated very quickly (in approximately 4 to 5 hours).
This pharmacokinetic profile therefore involves the administration of a substantial daily dose of 4 to 9 g, in doses repeated every 3 to 4 hours, and in particular in the middle of the night for narcoleptic patients, which results in a limited effectiveness due to the wide variations in plasma concentration as well as a risk of intolerance due to these same variations.
The existing galenic forms do not allow this profile to be improved.
For example, oral solutions are restrictive in terms of observance and can give rise to problems of stability and preservation. Moreover, since GHB is unstable in an acidic environment it is not possible to exclude the possibility of degradation of the GHB in the gastric environment and therefore a reduction of the bioavailability.